Influence of the HPA Axis on Anxiety-Related Processes: An RDoC Overview Considering Their Neural Correlates

Abstract

Purpose of review: Through a multidimensional lens, we review the literature on the link between anxiety-related processes, hypothalamic-pituitary-adrenal (HPA) axis functioning (with a particular focus on cortisol), and their neural correlates, using the Research Domain Criteria (RDoC) framework. This approach aims to capture the complexity of these processes by addressing their heterogeneity, multidimensionality, and underlying neurobiological mechanisms.

Recent findings: Within the RDoC framework, dysregulated cortisol (whether excessively elevated or blunted) has been linked to disruptions in different processes of the negative valence, positive valence, cognitive, social, arousal, and sensorimotor systems. These effects are associated with distinct neural substrates, including limbic, striatal, and prefrontal control areas. Different processes and neurobiological responses interact in complex, bidirectional ways, and understanding these interdependencies is essential for capturing the full nature of anxiety-related processes. These findings reinforce the value of adopting a multidimensional, RDoC-based framework, which allows for a more integrative and mechanistic understanding of mental health.

Keywords: Anxiety; Cortisol; HPA axis; RDoC; Stress; Transdiagnostic.

Fig. 1

Model illustrating the interaction between the six RDoC domains, the HPA axis, and other moderator factors. Red arrows represent direct (positive) associations, blue arrows negative associations, and green lines beneficial moderator effects (well-connected urban designs represented by the city icon for Negative Valence Systems, noradrenaline and dopamine for Positive Valence Systems, oxytocin for Social Processes, and neurofeedback training for Sensorimotor Systems). Meta-analytic activation maps for each RDoC domain were derived from Neurosynth [116] using the following keywords: negative affect (Negative Valence Systems), reward (Positive Valence Systems), working memory and cognitive control (merged into a single Cognitive Systems map), social (Social Processes), arousal (Arousal and Regulatory Systems) and sensorimotor (Sensorimotor Systems). Association Z-maps were thresholded at p FDR < 0.01. The HPA axis template was obtained from BioRender [117]. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FDR, false-discovery rate correction; HPA, hypothalamic-pituitary-adrenal axis; L, left; R, right